Sarcoidosis and Wound Healing After Cellulitis of the Lower Limb: Is Methotrexate Responsible for Skin Graft Failure?

The authors report the case of a 53-year-old man with diffuse cutaneous and mediastinal pulmonary sarcoidosis and well-controlled steroid-induced diabetes. He was hospitalized for cellulitis of his left leg. His standard treatment for sarcoidosis consisted of prednisone and methotrexate. Prednisone was stopped at his admission. He received antibiotics for 4 weeks to treat the cellulitis. In parallel, the leg wound was treated with daily silver sulfadiazine applications until necrosis removal, then by skin autografting. Four successive procedures were performed, but all failed despite lack of surgical problem or local infection. Methotrexate was stopped after the fourth grafting procedure failed; the fifth, and final, autografting procedure was successfully performed.

Sarcoidosis is a chronic multiorgan disease characterized by the formation of granulomas; it can be associated with recurrences of granulomas on cutaneous scars.^1,2 The authors report the case of a patient with a severe generalized form of sarcoidosis who presented with cellulitis of the leg. Treatment included cellulitis-associated antibiotics, and local debridement was followed by skin graft. The take of the skin graft failed due to the standard treatment of the sarcoidosis by methotrexate.

In November 2012, an overweight (body mass index, 35), 53-year-old man from the Democratic Republic of Congo was hospitalized for cellulitis of his left leg. Medical history showed diffuse cutaneous and mediastinal pulmonary sarcoidosis (diagnosed in 1992) with highly elevated angiotensin-converting enzyme (ACE, 120 IU/mL; normal value is 52), complicated by panuveitis in 1995, myelitis with paraplegia and urinary dysfunction in 2006, and atrioventricular block in 2010. Sarcoidosis had been perfectly controlled with prednisone and methotrexate since 2011. Interestingly, he had never presented any wound healing disturbances. At the onset of the cellulitis, standard treatment consisted of prednisone (5 mg/day), methotrexate (25 mg/week by subcutaneous injection since 2010), and folic acid (25 mg/week 3 days after methotrexate injections). In addition, the patient had an aseptic left femoral osteonecrosis for which he had undergone total hip arthroplasty in 1997, well-controlled steroid-induced diabetes since 2000 (glycated hemoglobin, 5.6%), and normal renal function (creatinine, 58 µmol/L). He did not show signs of induced hypogammaglobulinemia (15.8 g/L), lymphopenia (1710/mm³), or neutropenia (2820/mm³).

The patient was treated with amoxicillin/clavulanic acid and clindamycin over 4 weeks. All blood cultures remained negative, and his C-reactive protein (CRP) value decreased from 420 mg/L at admission to 43 mg/L at the end of antibiotic treatment. In parallel, daily silver sulfadiazine application was started from the day of admission to the first grafting procedure in January 2013, and it allowed progressive removal of skin and subcutaneous tissue necrosis of the left leg (Figure 1). According to the wound site on the lower limb, compressive garments were used in order to improve healing and to limit edema of the leg. 

Between January 2013 and April 2014, the same general surgeon performed 4 autografting procedures under general anesthesia using a split-thickness skin graft harvested from the same donor site on the ipsilateral thigh. Evolution of the 4 grafts was similar, marked by a successful take during the first 2 postoperative weeks, then by a major loss of the graft despite lack of surgical problem or local infection. By contrast, the donor site healed within 2 weeks.

In September 2014, given that sarcoidosis was under remission (ACE, 37 IU/mL) and autograft procedures had failed 4 times, methotrexate was stopped. Four months later, in January 2015, a fifth autografting procedure was successfully performed on the clinically uninfected wound (CRP, 76.9 mg/L). Two weeks later, the wound and the donor site were both completely healed. In January 2017, there was no sign of wound recurrence 24 months after wound closure. The skin graft was mechanically solid with a good trophicity (Figure 2), and the patient had no relapse of sarcoidosis. 

Methotrexate is considered the first choice in second-line therapeutics for sarcoidosis³; it is usually associated with hematologic, gastrointestinal, pulmonary, and hepatic toxicities.

Publications on wound healing and potential side effects of methotrexate are scarce. In a preclinical study on fresh wounds on the back of rats in 1965, Calnan and Davies⁴ found that wound healing was significantly depressed at doses corresponding to those used in humans. In contrast, methotrexate does not seem to affect wound healing after scheduled joint surgical procedures in patients with rheumatoid arthritis.⁵

To the best of the authors’ knowledge, the case reported herein is the first case of methotrexate administration and its possible impact on wound healing in sarcoidosis with inaugural skin involvement. Take of the graft was obtained when methotrexate was stopped, without any other confounding factors such as withdrawal of prednisone or better control of diabetes and sarcoidosis.

Affiliations: Faculté de Médecine, Paris Descartes, Paris, France; Service de Chirurgie Générale, Plastique et Ambulatoire, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, France; Service de Soins de Suite et Rééducation, Coubert, France; and Service de Médecine Interne, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris

Correspondence:
Sonia Gaucher, MD, PhD
Service de Chirurgie Générale
Plastique et Ambulatoire
AP-HP, HUPC, Hôpital Cochin
27 Rue du Faubourg Saint-Jacques, 
75014 Paris, France
sonia.gaucher@aphp.fr 

Disclosure: The authors disclose no financial or other conflicts of interest.